Antioxidant-mediated reversal of oxidative damage in mouse modeling of complex I inhibition.

Abstract

Mitochondrial dysfunction is a key component of various aging-related pathologies of the brain that result in dementia. As such, it provides an important avenue in development of therapeutic interventions for a host of neurological disorders. A requirement for functional mitochondrial respiratory chain complex I (CI), to accomplish the normal physiological processes regulating memory, seems intuitive. In the present study, a synthetic lipoylcarnitine antioxidant (PMX-500FI; 100 mg/kg/day po) was administered to female ICR mice (3-4-month old) that were subsequently treated with the mitochondrial CI inhibitor, rotenone (400 mg/kg/day). After 1 week, rotenone-induced impairment of neuronal function was evaluated in the hippocampus, a brain region that is involved in regulating memory formation. Electrophysiological recordings in live brain slices showed that long-term potentiation (LTP) was reduced by rotenone exposure (P < 0.05) while pretreatment with PMX-500FI maintained LTP similar to control levels (P > 0.05). Potentiation during theta burst stimulation (TBS) was similar among treatment groups (P > 0.05); however, neurotransmitter release, which increased in control mice after TBS, was lower in rotenone treated mice (P < 0.05), and was accompanied by reduced basal synaptic transmission (P < 0.05), increased proapoptotic signaling and decreased extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation (P < 0.05). For each of these determinations, pretreatment with PMX-500FI alleviated the harmful effects of rotenone. These results illustrate that treatment with antioxidant PMX-500FI is protective against rotenone-induced impairment of neuronal bioenergetics in the mouse hippocampus, in regard to both excitatory synaptic physiology and proapoptotic signaling. The protective effect of PMX-500FI against rotenone-induced disruption of cellular bioenergetics may have important therapeutic implications for treating aging-related dementia and other diseases related to mitochondrial dysfunction and/or oxidative damage.

• Authors: Kodeeswaran Parameshwaran, Michael H Irwin, Kosta Steliou, Vishnu Suppiramaniam, Carl A Pinkert
• Journal: Drug development research (Drug Dev Res) Vol. 76 Issue 2 Pg. 72-81 (Mar 2015) ISSN: 1098-2299 [Electronic] United States
• PMID: 25847731 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2015 Wiley Periodicals, Inc.

Chemical References

• Antioxidants
• PMX-500FI
• Rotenone
• Thioctic Acid
• Electron Transport Complex I
• Carnitine

Topics

• Animals
• Antioxidants (administration & dosage, pharmacology)
• Carnitine (administration & dosage, analogs & derivatives, pharmacology)
• Electron Transport Complex I (antagonists & inhibitors)
• Electrophysiological Phenomena
• Female
• Hippocampus (drug effects, physiopathology)
• Long-Term Potentiation (drug effects)
• Mice
• Mice, Inbred ICR
• Models, Animal
• Rotenone (toxicity)
• Signal Transduction (drug effects)
• Thioctic Acid (administration & dosage, analogs & derivatives, pharmacology)